Heterocyclic derivatives of 1-(1,3-dioxolan-2-ylmethyl)-1H-imidazoles

ABSTRACT

Heterocyclic derivatives of 1-(1,3-dioxolan-2-ylmethyl)-1H-imidazoles, useful as antifungal and antibacterial agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation-in-part of our copending application, Ser. No.764,265, filed Jan. 31, 1977, now abandoned.

BACKGROUND OF THE INVENTION

In U.S. Pat. Nos. 3,575,999, 3,936,470 and Belg. Pat. No. 835,579 thereare described a number of 1-(1,3-dioxolan-2-yl-methyl)-1H-imidazoles and1H-1,2,4-triazoles having antifungal and antibacterial properties. Thecompounds of this invention differ from the foregoing essentially by thenature of the complex substituent group present in the 4-position of thedioxolane moiety.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

This invention is concerned with novel 1H-imidazole and1H-1,2,4-triazole derivatives which may structurally be represented bythe formula: ##STR1## and the pharmaceutically acceptable acid additionsalts and stereochemically isomeric forms thereof, wherein:

Q is a member selected from the group consisting of CH and N;

Ar is a member selected from the group consisting of phenyl andsubstituted phenyl, said substituted phenyl having from 1 to 3substituents independently selected from the group consisting of halo,lower alkyl and lower alkyloxy; and the radical Y is a member selectedfrom the group consisting of:

A 1H-pyrrol-1-yl radical of the formula ##STR2##

A 1H-pyrazol-1-yl radical of the formula ##STR3## WHEREIN R₁ is selectedfrom the group consisting of hydrogen, lower alkyl, lower alkylthio andphenyl, and, R₂ is selected from the group consisting of hydrogen, loweralkyl and phenyl;

A 1H-imidazol-1-yl radical of the formula ##STR4## WHEREIN R₃ isselected from the group consisting of hydrogen, lower alkyl, phenyl,lower alkylthio, lower alkylsulfinyl and lower alkylsulfonyl, R₄ isselected from the group consisting of hydrogen, lower alkyl and phenyl,and, R₅ is selected from the group consisting of hydrogen and phenyl;

A 1H-1,2,4-triazol-1-yl radical of the formula ##STR5## wherein R₆ isselected from the group consisting of hydrogen and lower alkylthio, and,R₇ is selected from the group consisting of hydrogen, lower alkyl andphenyl;

a 4H-1,2,4-triazol-4-yl radical of the formula ##STR6## wherein R₈ isselected from the group consisting of hydrogen, lower alkyl, loweralkyloxy, lower alkylthio, lower alkylsulfinyl and lower alkylsulfonyl,and, R₉ is selected from the group consisting of hydrogen and loweralkyl;

a 2,3-dihydro-4H-1,2,4-triazol-4-yl radical of the formula ##STR7##wherein X is selected from the group consisting of O and S, and, R₁₀ andR₁₁ are each independently selected from the group consisting ofhydrogen and lower alkyl, provided that when said X is S then said R₁₁is hydrogen;

a 1H-1,2,3,4-tetrazol-1-yl radical of the formula ##STR8##

a 4,5-dihydro-5-thioxo-1H-1,2,3,4-tetrazol-1-yl radical of the formula##STR9##

It is understood that radicals of formula (f) wherein R₁₁ stands forhydrogen, as well as the radical of formula (h) may also exist undertheir tautomeric enol, respectively thienol, forms. Such enol andthienol forms, although not explicitely indicated in the abovestructures, are naturally intended to be within the scope of formula(I).

As used herein, the term "lower alkyl" denotes straight and branchchained hydrocarbon radicals having from 1 to 6 carbon atoms, such as,for example, methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl,butyl, pentyl, hexyl and the like; and the term "halo" is generic tohalogens of atomic weight less than 127, i.e. fluoro, chloro, bromo andiodo.

Preferred compounds within the scope of formula (I) are those wherein Qis CH and wherein the Y substituent is located at the position of thebenzene nucleus which is para to the dioxolanylmethoxy group.Particularly preferred are those compounds wherein Ar represents ahalophenyl or di-halophenyl radical, the most preferred being2,4-dichlorophenyl.

In order to simplify the structural representation of compounds (I) andof certain starting materials and intermediates used in the preparationthereof, the 2-Ar-2-(1H-imidazol-1-ylmethyl or1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl group wherein Ar is aspreviously defined, will hereafter be represented by the symbol D:##STR10##

The compounds of formula (I) wherein Y is as previously defined butother than a radical of the formula (f) wherein R₁₁ is hydrogen andother than a radical of formula (h), said Y being represented by Y₁ andsaid compounds by the formula (I-a), can be prepared by the reaction ofan appropriate reactive ester of the formula (II) with an appropriatelysubstituted phenol of formula (III). ##STR11## In formula (II), W hasthe meaning of a reactive ester residue such as, for example, halo,methylsulfonyloxy, 4-methylphenylsulfonyloxy and the like. The reactionof (II) with (III) is carried out under art-known conditions ofperforming O-alkylations with reactive esters. The reaction is generallycarried out in an appropriate reaction-inert organic solvent such as,for example, N,N-dimethylformamide, N,N-dimethylacetamide,hexamethylphosphoric triamide, dimethylsulfoxide, 4-methyl-2-pentanoneand the like, optionally in admixture with other reaction inert solventssuch as, for example, aromatic hydrocarbons, e.g., benzene,methylbenzene, dimethylbenzene and the like. Further it is advantageousto add to the reaction mixture an appropriate base such as, for example,an alkali metal hydride or carbonate, in order to enhance the rate ofthe reaction. Otherwise it may be advantageous to first convert thesubstituted phenol (III) into a metal salt thereof, preferably thesodium salt, in the usual manner, e.g., by the reaction of (III) withmetal bases such as sodium hydride, sodium hydroxide and the like, andto use thereafter said metal salt in the reaction with (II). Somewhatelevated temperatures are appropriate to enhance the reaction rate andmost preferably the reaction is carried out at from about 80° C. toabout 130° C.

Compounds of formula (I) wherein Y has the formula (c) wherein R₄ and R₅are as previously defined and R₃ is hydrogen, lower alkylthio, loweralkylsulfinyl or lower alkylsulfonyl, or, the formula (e), (f), (g) or(h), said Y being represented by Y₂ and said compounds by the formula(I-b), can also be prepared by cyclizing an appropriate intermediate(IV) wherein A is an amino group or a derivative thereof, with anappropriate cyclizing agent, and, if desired, introducing suitablesubstituents into the thus obtained heterocyclic compounds. ##STR12##

The nature of A in formula (IV), as well as the nature of the cyclizingagent to be used in the cyclization step, depend upon the meaning of Y₂in the desired compounds (I-b) as will be explained hereafter.

Compounds of formula (I-b) wherein Y₂ has the formula (c) wherein R₄ andR₅ have the previously indicated meaning and R₃ is hydrogen, loweralkylthio, lower alkylsulfinyl or lower alkylsulfonyl, said R₃ beingrepresented by R₃ ' and said compounds by (I-b-1), can be derived froman appropriate isothiocyanate of the formula (IV-a) by cyclizing thelatter with an appropriate aminoethanone or aminoacetaldehyde of theformula (V) and thereafter introducing appropriate substituents into thethus obtained 1H-imidazole-2-thiol of formula (VI) following art-knownprocedures. ##STR13##

The reaction of (IV-a) with (V) to produce (VI) is conveniently carriedout by stirring, preferably under heating, the reactants together in asuitable organic solvent, such as a lower alkanol, e.g. 2-propanol, inthe presence of an appropriate base such as, for example, an alkali orearth alkaline metal carbonate or hydrogen carbonate. The introductionof the desired R₃ ' substituents into (VI) can be accomplished bygenerally known procedures such as the following.

When R₃ ' stands for hydrogen the compounds (I-b-1) are easily obtainedby desulfurating (VI) in the usual manner, e.g., by treating the latterwith Raney-nickel or with diluted nitric acid. When R₃ ' stands forlower alkylthio the compounds (I-b-1) can be obtained by subjecting (VI)to a standard S-alkylation with a suitable reactive ester of the formula(VII)

    (lower alkyl)-W                                            VII

wherein W is as previously defined, or, with a di(lower alkyl) sulfate.When R₃ ' is a lower alkylsulfinyl or lower alkylsulfonyl group thecompounds (I-b-1) are obtained by subjecting the corresponding compoundswherein R₃ ' is lower alkylthio to an oxidation reaction with andappropriate oxidizing agent. Appropriate oxidizing agents to be usedtherefore include, for example, hydrogen peroxide, optionallysubstituted benzeneperoxoic acids, e.g. 3-chlorobenzeneperoxoic acid,and permanganate salts such as potassium permanganate. The degree ofoxidation, i.e. respectively to the sulfoxide or sulfone level, isdetermined by the ratio of the reagents. When sulfoxides are to beprepared about 2 equivalents of the oxidizing agent are to be used permole of sulfide while at least 4 equivalents are necessary to producesulfones. Oxidations with hydrogen peroxide and permanganate salts arepreferably carried out in acidic aqueous medium while oxidations withbenzeneperoxoic acids are preferably conducted in an appropriatereaction-inert organic solvent, e.g. a halogenated hydrocarbon such asdichloromethane.

Compounds of formula (I-b) wherein Y₂ has the formula (f) wherein R₁₁ ishydrogen, (I-b-2), are conveniently derived from an appropriateintermediate of the formula (IV-b) wherein X is as previously defined,using as a cyclizing agent an appropriate alkanimidamide of the formula(VIII) wherein R₁₀ has the previously indicated meaning, or an acidaddition salt thereof. ##STR14##

The cyclization reaction may be carried out according to methodologiesknown in the art, for example, by mixing and melting the reactantstogether, if desired in the presence of an appropriate reaction-inertorganic liquid having a relatively high boiling point such as, forexample, 1,1'-oxybis(2-methoxyethane).

Compounds of formula (I-b) wherein Y₂ has the formula (f) wherein X is Oand R₁₁ is lower alkyl, (I-b-4), can be prepared by N-alkylating acompound of the formula (I-b-2) wherein X stands for O, (I-b-3), with anappropriate reactive ester of formula (VII). ##STR15##

Said N-alkylation may be carried out in the usual manner, e.g. bystirring the reactants together, preferably at somewhat elevatedtemperatures in an appropriate organic solvent such as, for example,dimethylsulfoxide, in the presence of an appropriate base such as, forexample, an alkali metal hydride or carbonate.

The compounds of formula (I-b) wherein Y₂ has the formula (e), (I-b-6),can be prepared by introducing R₈ into an appropriate compound (I-b-2)wherein X stands for S and R₁₀ has the meaning of R₉ as previouslydefined, said starting compounds being represented by the formula(I-b-5). ##STR16##

Compounds of the formula (I-b-6) wherein R₈ is hydrogen, loweralkylthio, lower alkylsulfinyl or lower alkylsulfonyl are derived from(I-b-5) using similar procedures as described hereinbefore for thepreparation of compounds (I-b-1) starting from (VI). Those compounds offormula (I-b-6) wherein R₈ is lower alkyloxy can be derived from thecorresponding lower alkylsulfonyl substituted compounds by reacting thelatter with an appropriate lower alkanol to replace the loweralkylsulfonyl group by a lower alkyloxy group. The reaction ispreferably conducted at slightly elevated temperatures in an appropriaterelatively polar, organic solvent, such as dimethylsulfoxide, in thepresence of a strong metal base such as, for example, an alkali or earthalkaline metal hydride.

Compounds of formula (I-b) wherein Y₂ is a radical of formula (g),(I-b-7), can be prepared by the reaction of an intermediate of formula(IV) wherein A stands for an amino group, (IV-c), with an azide,preferably an alkali metal azide, e.g. sodium azide, and an appropriate1,1',1"-methylidynetris(oxy)tris(lower alkane) of formula (IX) in anappropriate acidic medium, e.g. acetic acid, preferably under heating.##STR17##

Compounds of formula (I-b) wherein Y₂ has the formula (h), (I-b-8), canbe obtained by the reaction of an isothiocyanate of formula (IV-a) withan appropriate azide, preferably sodium azide, in an appropriate organicsolvent, e.g. a lower alkanol such as methanol, ethanol, 2-propanol andthe like in the presence of alkali. ##STR18##

Said cyclization reaction may also be carried out by stirring (IV-a)with the azide in the presence of an appropriate quaternary ammoniumsalt, preferably N,N,N-triethylbenzenemethanaminium chloride, in asuitable solvent system such as, for example, water, preferably inadmixture with an appropriate organic solvent such as, for example,1,4-dioxane, to better solubilize the reactants.

The imidazole derivatives of formula (I), obtained in base form in theforegoing preparations, may be converted to their therapeutically usefulacid addition salts by reaction with an appropriate acid, as, forexample, an inorganic acid such as hydrohalic acid, i.e., hydrochloric,hydrobromic or hydroiodic acid; sulfuric, nitric or thiocyanic acid; aphosphoric acid; an organic acid such as acetic, propanoic,hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic,propanedioic, 1,4-butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic,2-hydroxy-1,4-butanedioic, 2,3-dihydroxy-1,4-butanedioic,2-hydroxy-1,2,3-propanetricorboxylic, benzoic, 3-phenyl-2-propenoic,α-hydroxybenzeneacetic, methanesulfonic, ethanesulfonic,2-hydroxyethanesulfonic, 4-methylbenzenesulfonic, 2-hydroxybenzoic,4-amino-2-hydroxybenzoic, 2-phenoxybenzoic or 2-acetyloxybenzoic acid.The salts are in turn converted to the corresponding free bases in theusual manner, e.g., by reaction with alkali such as sodium or potassiumhydroxide.

A number of the intermediates and starting materials used in theforegoing preparations are known compounds, others may be preparedaccording to art-known methodologies of preparing similar compounds andsome of them are novel and consequently their preparation will bedescribed hereafter.

Starting materials of formula (III) can in general be derived from thecorresponding methoxy-substituted compounds of formula (X) by convertingthe methoxy group of the latter into a hydroxy group by acid hydrolysisusing a strong non-oxidizing mineral acid, such as, for example,hydrobromic acid in acetic acid. ##STR19##

The intermediates of formula (X), used as starting materials herein canbe obtained by a variety of methods, depending on the nature of Y₁ insaid formula (X).

Intermediates of formula (X) wherein Y₁ has the formula (a), (b), (c) or(d), said Y₁ being represented by Y₁ ' and said intermediates by (X-a),can conveniently be prepared by the reaction of an appropriatehalo-methoxybenzene of formula (XI) with an appropriate azole of formula(XII). ##STR20##

The reaction of (XI) with (XII) is carried out according to art-knownprocedures, e.g., by stirring the reactants together for from severalhours to several days in an appropriate organic solvent such as, forexample, N,N-Dimethylformamide, N,N-dimethylacetamide,hexamethyphosphoric triamide, dimethylsulfoxide and the like, mostpreferably in the presence of an appropriate copper (I) salt, e.g. thechloride or the bromide, to enhance the reaction rate.

Those intermediates of formula (X) wherein Y₁ has the formula (a) aswell as the corresponding phenols of formula (III) can also be preparedaccording to the method described in Ber. 95, 2270 (1962).

Intermediates of formula (X) wherein Y₁ has the formula (b), (X-b), mayalso be prepared by the reaction of an appropriate(methoxyphenyl)hydrazine of formula (XIII), which is usually employed inthe form of an acid addition salt, with an appropriate dione of formula(XIV) wherein R₁ and R₂ are as previously defined. ##STR21##

The reaction of (XIII) with (XIV) is conveniently carried out bystirring and refluxing the reactants together in an appropriate organicsolvent, e.g. a lower alkanol such as ethanol, preferably but notnecessarily in the presence of an appropriate base such as, for example,an alkali metal carbonate, e.g., potassium carbonate. When R₁ stands forhydrogen, the adjacent carbonyl group of (XIV) is preferably ketalizedprior to reacting said (XIV) with (XIII) in order to obtain a pyrazolederivative wherein R₂ is unambigously located at the 5-position.Mixtures of position isomers which can otherwise be obtained when usingunketalized aldehydes or ketones of formula (XIV) may be subjected tostandard isolation and purification procedures to separate the pureconstituents from each other.

Intermediates of formula (X) wherein Y₁ stands for a radical of theformula (c) wherein R₃ has the meaning of R₃ ' as previously defined,(X-c), can also be derived from an appropriate isothiocyanate of theformula (XV) by cyclizing the latter with an appropriate aminoethanoneof the formula (V) and thereafter introducing the desired R₃'-substituents into the thus obtained (XVI) following similar proceduresas previously described herein for the preparation of compounds (I-b-1)starting from (IV-a) ##STR22##

Intermediates of formula (X) wherein Y₁ stands for a radical of formula(d), (X-d), can also be prepared starting from a appropriate1-(methoxyphenyl)-1H-1,2,4-triazole-3-thiol of formula (XVII) bydesulfurating or S-alkylating the latter in the usual manner to obtain(X-d) wherein R₆ is hydrogen or lower alkylthio. ##STR23##

The 1H-1,2,4-triazole-3-thiols of formula (XVII) used as startingmaterials herein can be derived from an appropriate2-(methoxyphenyl)hydrazinecarbothioamide of formula (XVIII) by cyclizingthe latter with an appropriate carboxylic acid of the formula ##STR24##or a functional derivative thereof, such as, for example, an acylhalide, an ester, or preferably an imidamide of the formula ##STR25##The reaction is conveniently carried out by stirring and heating thereactants together in an appropriate organic solvent, e.g. a loweralkanol such as, for example, 2-propanol, butanol and the like.

Alternatively the same compounds (XVII) can be obtained by firstacylating (XVIII) with an appropriate anhydride (XX) or acyl halide(XIX-b) derived from an acid of formula (XIX), to obtain an intermediateof formula (XXI), and, thereafter cyclizing the latter by stirring andheating (XXI) in alcoholic alkali. The foregoing reaction areschematically represented as follows: ##STR26##

Still another method of preparing the compounds of formula (XVII) is byreacting a hydrazine hydrochloride of formula (XIII-a) with an acylisothiocyanate of formula (XXII) in N,N-diethylethanamine, washing thereaction mixture with water, evaporating off the solvent and thereafterstirring and heating the residue in a mixture of dichloromethane andethanol in the presence of alkali. ##STR27##

intermediates of formula (X) wherein Y₁ is a radical of the formula (e)or (f) can easily be derived from aN-(methoxyphenyl)hydrazinecarboxamide or carbothioamide of the formula##STR28## by the application of similar procedures as previouslydescribed herein for the preparation of compounds (I-b-2), (I-b-4) and(I-b-6) starting from IV-b).

Intermediates of formula (X) wherein Y₁ is a radical of formula (g) canbe derived from a methoxybenzenamine of the formula ##STR29## followingthe procedures described herein for the preparation of compounds (I-b-7)starting from (IV-c).

The precursor materials of the formulae (XIII), (XV) and (XXIV) hereinare generally known and may be prepared following methods described inthe literature.

The precursor materials of formula (XVIII) are easily prepared by thereaction of the corresponding hydrazine hydrochloride with potassiumisothiocyanate, according to the procedure described in C.A., 59, 8651 b(1963) wherein the 4-substituted analog is specifically described.

The precursor materials of formula (XXIII) wherein X stands for S,(XXIII-a), are described in C.A., 18, 378⁸ (1924); C.A., 47, 3342i(1953); C.A., 56, P 3681a (1962); C.A., 51, 12016h (1957); and J. Am.Chem. Soc., 70, 3439 (1948).

The precursor materials of formula (XXIII) wherein X stands for O,(XXIII-b), are easily obtained by the reaction of a phenyl(methoxyphenyl)carbamate (XXV) with hydrazine hydrate. ##STR30##

The carbamates of formula (XXV) are conveniently prepared by thereaction of a benzenamine of formula (XXIV) with phenylcarbonochloridate. The compound of formula (XXIII-b) wherein the methoxygroup is located at the para-position is described in C.A., 31, 3891⁸(1937).

Starting materials of formula (II) wherein Q stands for CH and methodsof preparing the same are described in Belg. Pat. No. 837,831. Ingeneral the reactive esters of formula (II) can be prepared along thefollowing sequence of reactions.

An appropriate 1-Ar-2-bromoethanone of formula (XXVI) is subjected to aketalization reaction with 1,2,3-propanetriol following methodologiesanalogous to those described in Synthesis, 1974 (I), 23.

In a preferred manner of carrying out the reaction both reactants arerefluxed together for several hours with azeotropic water removal in anappropriate organic solvent, preferably in the presence of a simplealcohol, such as, for example, ethanol, propanol, butanol, pentanol andthe like, and in the presence of an appropriate strong acid such as4-methylbenzenesulfonic acid. Suitable organic solvents are, forexample, aromatic hydrocarbons, such as benzene, methylbenzene,dimethylbenzene and the like and saturated hydrocarbons, such ascyclohexane.

The thus obtained dioxolane (XXVII) is then reacted with benzoylchloride to obtain a benzoate of the formula (XXVIII) and the latter issubsequently reacted with 1H-imidazole or 1H-1,2,4-triazole. Saidreaction is preferably carried out by stirring and heating the reactantstogether in a suitable organic solvent, e.g. N,N-dimethylformamide, inthe presence of an appropriate strong metal base, e.g. sodiummethanolate to obtain an intermediate of the formula XXIX). The desiredreactive esters of formula (II) are then conveniently prepared by firsthydrolyzing (XXIX) in alkaline medium and thereafter converting thehydroxy group of the thus obtained (XXX) into a reactive ester thereofaccording to methodologies generally known in the art. For example,methanesulfonates and 4-methylbenzenesulfonates are convenientlyprepared by the reaction of the alcohol with methanesulfonyl chloride or4-methylbenzenesulfonyl chloride and halides may be prepared by thereaction of the alcohol with an appropriate halogenating agent such as,for example, sulfuryl chloride, phosphor pentachloride, phosphorpentabromide, phosphoryl chloride and the like. When the reactive esteris an iodide, it is preferably prepared from the corresponding chlorideor bromide by the replacement of that halogen with iodine.

The foregoing reactions may be illustrated as follows: ##STR31##

Intermediates of formula (IV) may be obtained along the followingreaction sequence.

An appropriate reactive ester of the formula (II) is reacted in theusual manner with a N-(hydroxyphenyl)acetamide, (XXXI), to obtain anintermediate of formula (XXXII), the amide group of which is subjectedto alkaline hydrolysis, e.g., with alkanolic alkali, to obtain thecorresponding amine, (IV-c).

Intermediates of formula (IV) wherein A stands for isothiocyanato,(IV-a), are easily derived therefrom by the application of art-knownmethods of preparing isothiocyanates from amines, e.g., by the reactionof (IV-c) with carbon disulfide andN,N'-methanetetraylbis(cyclohexanamine) in pyridine.

Intermediates (IV) wherein A stands for a hydrazinecarbothioamide group,(IV-b-1), can be derived from (IV-a) by the reaction thereof withhydrazine hydrate.

Intermediates (IV) wherein A stands for a hydrazinecarboxamide group,(IV-b-2), can be prepared by first converting (IV-c) into a phenylcarbamate (XXXIII) by the reaction of the former with phenylcarbonochloridate and subsequent reaction of said (XXXIII) withhydrazine hydrate.

The foregoing reactions are schematically illustrated hereafter.##STR32##

The intermediates of formulae (IV-b-1) and (IV-b-2) and thestereochemically isomeric forms thereof are deemed to be novel, and, asuseful intermediates herein they constitute an additional feature ofthis invention. The intermediates of formulae (IV-a), (XXXII), (IV-c)and (XXXIII) are also deemed to be novel and, apart from their utilityas intermediates herein, they possess themselves antifungal andantibacterial properties, and, as such they are described and claimed inour U.S. Pat. Application Ser. No. 764,263 filed Jan. 31, 1977, nowabandoned and subsequently filed as a continuation-in-part applicationSer. No. 853,728, filed Nov. 21, 1977.

From formula (I) it is evident that the compounds of this invention haveat least two asymmetric carbon atoms in their structures, namely thoselocated in the 2- and 4-position of the dioxolane nucleus, andconsequently they can exist under different stereochemically isomericforms. The stereochemically isomeric forms of (I) annd thepharmaceutically acceptable acid addition salts thereof are intended tobe within the scope of this invention.

The diastereomeric racemates of (I), denoted as cis and trans formsrespectively, according to the rules described in C.A., 76, Index Guide,Section IV, p. 85 (1972), may be obtained separately by conventionalmethods. Appropriate methods which may advantageously be employedtherefore include, for example, selective crystallization andchromatographic separation, e.g. column-chromatography.

Since the stereochemical configuration is already fixed in theintermediates (II) and (IV) it is also possible to separate cis andtrans forms at this or even an earlier stage, whereupon thecorresponding forms of (I) may be derived therefrom in the previouslyindicated manner. The separation of cis and trans forms of suchintermediates may be performed by conventional methods as describedhereabove for the separation of cis and and trans forms of the compounds(I).

It is evident that the cis and trans diastereomeric racemates may befurther resolved into their optical isomers, cis(+), cis(-), trans(+)and trans(-) by the application of methodologies known to those skilledin the art.

The compounds of formula (I) and the pharmaceutically acceptable acidaddition salts thereof are useful agents in combatting fungi andbacteria. For example, said compounds and acid addition salts thereofwere found to be highly active against a wide variety of fungi such as,for example, Microsporum canis, Ctenomyces mentagrophytes, Trichophytonrubrum, Phialophora verrucosa, Cryptococcus neoformans, Candidatropicalis, Candida albicans, Mucor species, Aspergillus fumigatus,Sporotrichum schenckii and Saprolegnia species, and against bacteriasuch as, for example, Erysipelotrix insidiosa, Staphylococci such asStraphylococcus hemolyticus and Streptococci such as Streptococcuspyogenes. In view of their potent, local as well as systemic,antimicrobial activity the compounds of this invention constitute usefultools for the destruction or prevention of the growth of fungi andbacteria and more particularly they can effectively be used in thetreatment of subjects suffering from such microorganism.

The strong antimicrobial activity of the compounds (I) is clearlyevidenced by the data obtained in the following experiments, which datais only given to illustrate the useful antimicrobial properties of allthe compounds (I) and not to limit the invention either with respect tothe scope of susceptible microorganisms nor with respect to the scope offormula (I).

Experiment A: Activity of compounds (I) against vaginal candidosis inrats

Female Wistar rats of ± 100 g body weight were used. They wereovariectomized and hysterectomized and after three weeks of recovery,100 μg of oestradiol undecylate in sesame oil was given subcutaneouslyonce a week for 3 consecutive weeks. The thus induced pseudooestrus wascontrolled by microscopic examination of vaginal smears. Food and waterwere left available ad libitum.

The rats were infected intravaginally with 8.10⁵ cells of Candidaalbicans, grown on Sabouraud broth for 48 hours at 37° C. and dilutedwith saline. The date of infection varied from day +25 to day +32 aftersurgical intervention, depending on the appearance of signs of inducedpseudo-oestrus.

The drugs under investigation were administered orally once a day fortwo days starting from the day of infection. For each experiment therewere placebo treated controls. The results were assessed by takingvaginal smears with sterile swabs on several days after the infection.The swabs were put into Sabouraud broth in petri-dishes and incubatedfor 48 hours at 37° C. If no growth of Candida albicans occured, i.e.,when the animals were negative at the end of the experiment, this wasdue to drug administration because it never happened in placebo treatedcontrols.

The tables I and II below give the lowest oral dose of the drug underinvestigation which was found active at the 14th day after infection.

Experiment B: Activity of compounds (I) against crop candidosis inturkeys

Turkeys of 14 days old were infected in the crop with 4·10⁶ Candidaalbicans cells, grown on Sabouraud broth for 48 hours at 37° C. anddiluted with saline. The volume of the inoculum was 1 ml. The drug underinvestigation were premixed in 500 mg of lacton and thereafter admixedin 1000 g of meal without any additives. The concentration of the drugunder investigation in the meal was expressed in mg/kg.

The animals were given the medicated feed for 13 consecutive daysstarting on the day of infection. At the end of the experiment allanimals were sacrificed. At autopsy the crops were removed, emptied andgrinded in an ultra-turrax mixer in 15 ml of sterile saline. Colonycounting was done on Sabouraud agar and the results given in Tables Iand Ii represent the ED₅₀, i.e., the dose of the drug whereby the cropsof 50% of the animals were completely negative for Candida albicans.

                                      TABLE I                                     __________________________________________________________________________     ##STR33##                                                                                                  Vaginal candidosis                                                                      Crop candidosis                                                     in rats:  in Turkeys:                                                         lowest effective                                                                        ED.sub.50 in                                                        dose in   mg/kg of                                Y               Base or Salt                                                                              mg/kg.    feed.                                 __________________________________________________________________________     ##STR34##        base        1.25      8                                      ##STR35##        base        1.25      16                                     ##STR36##        base        2.50      125                                    ##STR37##        base        2.50      16                                     ##STR38##        base        10        125                                    ##STR39##        2 . HNO.sub.3                                                                             5         125                                    ##STR40##        base        <10       --                                     ##STR41##        base        <10       --                                     ##STR42##        base        <10       --                                     ##STR43##        HNO.sub.3   1.25      --                                     ##STR44##        base        5         --                                     ##STR45##        base        5         31                                     ##STR46##        base        2.5       --                                     ##STR47##        base        2.5       --                                     ##STR48##        base        10        8                                      ##STR49##        2HNO.sub.3  5         --                                     ##STR50##        2HNO.sub.3  5         31                                     ##STR51##        2HNO.sub.3  5         31                                     ##STR52##        2HNO.sub.3  --        31                                     ##STR53##        2HNO.sub.3  --        31                                     ##STR54##        2HNO.sub.3  1.25      16                                     ##STR55##        HNO.sub.3 . H.sub.2 O                                                                     10        --                                     ##STR56##        HNO.sub.3   2.5       --                                     ##STR57##        HNO.sub.3   2.5       --                                     ##STR58##        2HNO.sub.3  2.5       --                                     ##STR59##        2HNO.sub.3  1.25      8                                      ##STR60##        base H.sub.2 O                                                                            5         --                                     ##STR61##        2(COOH).sub.2                                                                             2.5       31                                     ##STR62##        2HNO.sub.3  5         8                                      ##STR63##        11/2 (COOH).sub.2                                                                         2.5       --                                     ##STR64##                                                                                       ##STR65##  10        16                                     ##STR66##        base        --        31                                    __________________________________________________________________________

                                      TABLE II                                    __________________________________________________________________________    Compounds of formula I                                                                           Base  Vagingal candidosis in rats:                                            or    lowest effective dose in                                                                     Crop candidosis in Turkeys:           Q  Ar      Y       Salt  mg/kg          ED.sub.50 in mg/kg in                 __________________________________________________________________________                                            feed                                  CH 4-OCH.sub.3C.sub.6 H.sub.4                                                             ##STR67##                                                                            base  5              --                                    CH 2,4-Cl.sub.2C.sub.6 H.sub.3                                                            ##STR68##                                                                            2(COOH).sub.2                                                                       2.5            --                                    N  2,4-Cl.sub.2C.sub.6 H.sub.3                                                            ##STR69##                                                                            base  1.25           8                                     __________________________________________________________________________

In view of their antifungal and antibacterial properties this inventionprovides valuable compositions comprising the subject compounds offormula (I) or acid addition salts thereof as the active ingredient in asolvent or a solid, semi-solid or liquid diluent or carrier, and, inaddition, it provides an effective method of combatting fungal orbacterial growth by use of an effective antifungal or antibacterialamount of such compounds (I) or salts thereof. Antifungal andantibacterial compositions comprising an effective amount of an activecompound (I), either alone or in combination with other activetherapeutic ingredients, in admixture with suitable carriers may bereadily prepared according to conventional pharmaceutical techniques forthe usual routes of administration.

Preferred compositions are in dosage unit form, comprising per dosageunit an effective quantity of the active ingredient in admixture withsuitable carriers. Although the amount of the active ingredient per unitdosage may vary within rather wide limits, dosage units comprising fromabout 50 to about 500 mg and more particularly from about 100 to about250 mg of the active ingredient are preferred.

The following examples are intended to illustrate and not to limit thescope of the present invention.

Unless otherwise stated all parts therein are by weight.

EXAMPLE I

A mixture of 16.4 parts of 2-methyl-1H-imidazole, 37.4 parts of1-bromo-4-methoxybenzene, 1 part of copper-(I)bromide, 20 parts ofpotassium carbonate and 270 parts of N,N-dimethylformamide is stirredand refluxed for one week. The reaction mixture is cooled, poured ontowater and the whole is extracted with 2,2'-oxybispropane. The extract iswashed twice with diluted hydrochloric acid solution. The acid aqueousphase is separated and alkalized with sodium hydroxide. The product isextracted twice with 2,2'-oxybispropane. The combined extracts aredried, filtered and evaporated, yielding 4 parts (41%) of1-(4-methoxyphenyl)-2-methyl-1H-imidazole as a residue.

A mixture of 4 parts of 1-(4-methoxyphenyl)-2-methyl-1H-imidazole and37.5 parts of hydrobromic acid solution 48% is stirred and refluxedovernight. After cooling, the reaction mixture is evaporated. Theresidue is triturated in a mixture of 2-propanone and2,2'-oxybispropane. The product is filtered off and crystallized from amixture of ethanol and 2,2'-oxybispropane, yielding 3.8 parts (69%) of4-(2-methyl-1H-imidazol-1yl)phenol monohydrobromide; mp. 181-205° C.

EXAMPLE II

A mixture of 19.2 parts of 2-ethyl-1H-imidazole, 37.4 parts of1-bromo-4-methoxybenzene, 1 part of copper(I)iodide, 20 parts ofpotassium iodide and 180 parts of N,N-dimethylacetamide is stirred andrefluxed for one week. The reaction mixture is cooled, diluted withwater and the product is extracted with 2,2'-oxybispropane. Afterfiltration over hyflo, the extract is separated from the aqueous phaseand acidified with a concentrated nitric acid solution. The formednitrate salt is filtered off and crystallized from a mixture of ethanoland 2,2'-oxybispropane, yielding 6.2 parts (12%) of2-ethyl-1-(4-methoxyphenyl)-1H-imidazole mononitrate; mp. 132.6° C.

A mixture of 5.2 parts of 2-ethyl-1-(4-methoxyphenyl)-1H-imidazole and75 parts of hydrobromic acid solution 48% in glacial acetic acid isstirred and refluxed overnight. The solvent is evaporated and theresidue is triturated in 2-propanone. The product is filtered off anddried, yielding 6.1 parts (100%) of 4-(2-ethyl-1H-imidazol-1-yl)phenolmonohydrobromide.

EXAMPLE III

A mixture of 28.8 parts of 2-phenyl-1H-imidazole, 37.4 parts of1-bromo-4-methoxybenzene, 20 of potassium carbonate and 180 parts ofN,N-dimethylacetamide is stirred for one week at reflux temperature. Thereaction mixture is cooled, poured onto water and the product isextracted twice with 2,2'-oxybispropane. The combined extracts aredried, filtered and evaporated, yielding 10 parts (25%) of1-(4-methoxyphenyl)-2-phenyl-4H-imidazole as a residue.

A mixture of 10 parts of 1-(4-methoxyphenyl)-2-phenyl-1H-imidazole and150 parts of a hydrobromic acid solution 48% is stirred and refluxedovernight. The solvent is removed in vacuo and the residue is dissolvedin methanol. The solution is saturated with a small excess of sodiumhydroxide. After the addition of 2,2'-oxybispropane, the product isprecipitated. It is filtered off and dried, yielding 7.9 parts (76%) ofsodium 4-(2-phenyl-1H-imidazol-1-yl)phenolate.

EXAMPLE IV

A mixture of 13.8 parts of 1H-1,2,4-triazole, 18.7 parts of1-bromo-4-methoxybenzene, 5 parts of potassium carbonate, 0.5 parts ofcopper (I)chloride and 90 parts of N,N-dimethylformamide is stirred andrefluxed for 2 days. The reaction mixture is cooled and poured ontowater. The product is extracted twice with benzene. The combinedextracts are washed with water, dried filtered and evaporated. Theresidue is purified by column-chromatography over silica gel usingtrichloromethane as eluent. The pure fractions are collected and theeluent is evaporated. The residue is triturated in 2,2'-oxybispropane.The product is filtered off and dried, yielding 7.8 parts (44.5%) of1-(4-methoxyphenyl)-1H-1,2,4-triazole; mp. 99.4° C.

A mixture of 8 parts of 1-(4-methoxyphenyl)-1H-1,2,4-triazole and 150parts of a hydrobromic acid solution 48% is stirred and refluxedovernight. The reaction mixture is evaporated and the residue istriturated in 2-propanone. The product is filtered off and crystallizedfrom ethanol, yielding 5.5 parts (74%) of4-(1H-1,2,4-triazol-1-yl)phenol; mp. 255.4° C.

EXAMPLE V

A mixture of 1.7 parts of N-(4-hydroxyphenyl)acetamide, 4.2 parts ofcis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethylmethanesulfonate, 2 parts of potassium carbonate and 68 parts ofN,N-dimethylformamide is stirred overnight at 100° C. The reactionmixture is cooled and poured onto water. The product is extracted twicewith trichloromethane. The combined extracts are washed twice withwater, dried, filtered and evaporated. The residue is triturated in amixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product isfiltered off and crystallized from 4-methyl-2-pentanone, yielding 2.8parts (61%) ofcis-N-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}acetamide;mp. 180.5° C.

A mixture of 8.9 parts ofcis-N-{4-[2-(2,4-dichloropheny)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}acetamide,1.5 parts of potassium hydroxide and 80 parts of 1-butanol is stirredand refluxed overnight. The reaction mixture is evaporated and water isadded to the residue. The precipitated product is filtered off andcrystallized from methylbenzene, yielding 6.6 parts (82% ofcis-4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]benzenamine;mp. 164.4° C.

EXAMPLE VI

To a stirred and cooled (ice-bath) solution of 8.4 parts ofcis-4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]benzenaminein 75 parts of pyridine and 112 parts of trichloromethane are addeddropwise 3.5 parts of phenyl carbonochloridate. Upon completion,stirring is continued for 3 hours at room temperature. The reactionmixture is poured onto water and the product is extracted twice withtrichloromethane. The combined extracts are dried, filtered andevaporated. The residue is triturated in a mixture of 1,1'-oxybisethaneand 2,2'-oxybispropane. The product is filtered off and crystallizedfrom 4-methyl-2-pentanone, yielding 8.6 parts ofcis-phenyl{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}carbamate;mp. 170.6° C.

A mixture of 50 parts of hydrazine hydrate, 6 parts ofcis-phenyl{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}carbamateand 100 parts of 1,4-dioxane is stirred and refluxed for 2 hours. Thereaction mixture is cooled, poured onto water and stirred till theproduct is precipitated. It is filtered off and crystallized fromethanol, yielding 4.8 parts (91%) of cisN-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}hydrazinecarboxamidehemihydrate; mp. 187.5° C.

EXAMPLE VII

To a stirred and cooled (ice-salt bath) solution of 13 parts of carbondisulfide and 2.1 parts of N,N'-methanetetraylbis[cyclohexanamine] in 15parts of pyridine is added dropwise a solution of 4.2 parts ofcis-4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]benzenaminein 25 parts of pyridine at a temperature between -10° C. and -5° C. Uponcompletion, stirring is continued first at -10°- -5° C. for 3 hours andfurther at room temperature for one hour. The reaction mixture isevaporated. The residue is dissolved in 20 parts of acetic acid. Thesolution is stirred and 50 parts of water are added. The formedprcipitate is filtered off and the filtrate is neutralized withpotassium carbonate. The product is extracted with 1,1'-oxybisethane.The extract is dried, filtered and evaporated. The residue is purifiedby column-chromatography over silica gel using trichloromethane aseluent. The pure fractions are collected and the eluent is evaporated.The residue is crystallized from a mixture of 4-methyl-2-pentanone and2,2'-oxybispropane. The product is filtered off and dried, yielding 3.2parts (69%) ofcis-1-[2-(2,4-dichlorophenyl)-4-(4-isothiocyanatophenoxymethyl)-1,3-dioxolan-2-methyl]-1H-imidazole;mp. 136° C.

To a stirred solution of 14 parts ofcis-1-[2-(2,4-dichlorophenyl)-4-(4-isothiocyanatophenoxymethyl)-1,3-dioxolan-2-ylmethyl]-1H-imidazolein 160 parts of methanol are added 7.5 parts of hydrazine hydrate.Stirring is continued for two hours at room temperature. Theprecipitated product is filtered off, washed with methanol, dried andcrystallized from ethanol, yielding 10.7 parts ofcis-N-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}hydrazinecarbothioamide;mp. 167.3° C.

EXAMPLE VIII

A mixture of 1.8 parts of 4-(1H-imidazol-1-yl)phenol, 4.2 parts ofcis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethylmethanesulfonate, 2 parts of potassium carbonate and 68 parts ofN,N-dimethylformamide is stirred overnight at 100° C. The reactionmixture is cooled onto water. The product is extracted twice withbenzene. The combined extracts are washed with water, dried, filteredand evaporated. The residue is converted into the nitrate salt in2-propanone. The salt is filtered off and crystallized from ethanol,yielding 3.5 parts (59%) ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-imidazolenitrate; mp. 191.1° C.

EXAMPLE IX

Following the procedure of Example VIII and using equivalent amount ofthe appropriate starting materials, the following compounds are obtainedin free base form or in the form of an acid addition salt after reactionof the free base with an appropriate acid:

cis-1-{2-(2,4-dichlorophenyl)-4-[4-(1H-pyrrol-1-yl)-phenoxymethyl]-1,3-dioxolan-2-ylmethyl}-1H-imidazole;mp. 149.8° C.;

cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-pyrazole;mp. 135.6° C.; and

cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-1,2,4-triazole;mp. 140.1° C.

EXAMPLE X

A mixture of 2.8 parts of sodium4-(2-phenyl)-1H-imidazol-1-yl)phenolate, 4.2 parts ofcis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethylmethanesulfonate and 100 parts of dimethylsulfoxide is stirred overnightat 100° C. The reaction mixture is cooled and poured onto water. Theproduct is extracted twice with benzene. The combined extracts aredried, filtered and evaporated. The residue is converted into thenitrate in 4-methyl-2-pentanone and 2,2'-oxybispropane. The salt isfiltered off and crystallized from a mixture of ethanol and2,2'-oxybispropane, yielding 3.7 parts (55%) of cis1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-2-phenyl-1H-imidazoledinitrate; mp. 191.8° C.

EXAMPLE XI

To a stirred suspension of 1.6 parts of sodium hydride dispersion 78% in200 parts of dimethylsulfoxide and 45 parts of benzene are added 7.6parts of 4-(1H-imidazol-1-yl)phenol and stirring is continued for onehour at 50° C. Then there are added 16.8 arts ofcis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethylmethanesulfonate. After stirring for 6 hours at 100° C., the reactionmixture is cooled, poured onto water and the product is extracted withbenzene. The extract is dried, filtered and evaporated. The residue istriturated in 4-methyl-2-pentanone. The product is filtered off andcrystallized from 4-methyl-2-pentanone, yielding 14.7 parts (78%) ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-imidazole;mp. 142.9° C.

EXAMPLE XII

Following the procedure of Example XI there are preparedcis-1-{4-[2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-2-methyl-1H-imidazoledinitrate; mp. 183.9° C. by the reaction of4-(2-methyl-1H-imidazol-1-yl)phenol monohydrobromide withcis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethylmethanesulfonate; andcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-2-ethyl-1H-imidazoleethanedioate (1:2); mp. 185.6° C. by the reaction of the latter with4-(2-ethyl-1H-imidazol-1-yl)phenol.

EXAMPLE XIII

A mixture of 4 parts of ethanimidamide hydrochloride, 5 parts of cisN-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}hydrazinecarboxamidehemihydrate and 4 parts of sodium acetate is melted together in anoil-bath at 160° C. for 30 minutes. The melt is dissolved intrichloromethane. The solution is washed with water, dried, filtered andevaporated. The residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and methanol (95:5 by volume) aseluent. The pure fractions are collected and the eluent is evaporated.The residue is crystallized from 2-propanol, yielding 2 parts (39%) ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one;mp. 223.8° C.

EXAMPLE XIV

6 Parts of cisN-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}hydrazinecarboxamine.hemihydrateand 5 parts of methanimidamide acetate are mixed and melted togetherunder IR-radiation. The melt is cooled and dissolved intrichloromethane. The solution is washed with water and treated withactivated charcoal. The latter is filtered off and the filtrate isevaporated. The residue is triturated in a mixture of 2-propanol and1,1'-oxybisethane. The product is filtered off and crystallized from2-propanol, yielding 3.6 parts (60%) ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4ylmethoxy]phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-one;mp. 212.8° C.

EXAMPLE XV

To a stirred solution of 1.2 parts of 1-bromopropane and 4 parts ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-onein 50 parts of dimethylsulfoxide are added 0.32 parts of sodium hydridedispersion 78%. Stirring is continued first for one hour at roomtemperature and further for one hour at 50° C. The reaction mixture ispoured onto water and the product is extracted twice with1,1'-oxybisethane. The combined extracts are washed with water, dried,filtered and evaporated. The residue is purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane and methanol (98.2 by volume) as eluent. The purefractions are collected and the eluent is evaporated. The residue iscrystallized from a mixture of 4-methyl-2-pentanone and2,2'-oxybispropane, yielding 3 parts (70%) ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}- 2,4-dihydro-2-propyl-3H-1,2,4-triazol-3-one; mp.143.3° C.

EXAMPLE XVI

Following the procedure of Example XV there are preparedcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-phenyl}-2,4-dihydro-2-(1-methylethyl)-3H-1,2,4-triazol-3-one;mp. 145.7° C. by the reaction ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-onewith 2-bromopropane;cis-4-{4-[2(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-2,4-dihydro-2-methyl-3H-1,2,4-triazol-3-one;mp. 144.2° C. by the reaction ofthe former with iodomethane; andcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-2,4-dihydro-5-methyl-2-propyl-3H-1,2,4-triazol-3-onemononitrate; mp. 180.2° C. by the reaction ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one with 1-bromopropane.

EXAMPLE XVII

5 Parts of methanimidamide acetate and 5 parts ofcis-N-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}hydrazinecarbothioamideare mixed intimately in a mortar and then heated for about 30 minutes at160° C. The reaction mixture is cooled, water is added and the productis extracted with trichloromethane. The extract is dried, filtered andevaporated. The residue is crystallized frm 2-propanol, yielding 2.5parts (50%) ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4H-1,2,4-triazol-3-thiol;mp. 235.3° C.

EXAMPLE XVIII

A mixture of 5 parts ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1-H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4H-1,2,4-triazole-3-thiol,5 parts of Raney-nickel catalyst and 200 parts of methanol is stirredand refluxed for one hour. The solution is decanted while hot. 450 Partsof trichloromethane are added. The organic phase is dried, filtered andevaporated. The residue is crystallized from 4-methyl-2-pentanone. Theproduct is filtered off and dried, yielding 2 parts (42%) ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4H-1,2,4-triazole;mp. 153.4° C.

EXAMPLE XIX

Following the procedure of Example XI and using equivalent amounts ofthe appropriate starting materials the following compounds are stillobtained:

trans-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-imidazole;

trans-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-1,2,4-triazole;

trans-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-pyrazole;

1-{4-[2-(4-chlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-imidazole;

1-{4-[2-(4-bromophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-imidazole;

1-{4-[2-(4-fluorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-imidazole;

1-{4-[2-(2,6-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-imidazole;

1-{4-[2-(1H-imidazol-1-ylmethyl)-2-(4-methylphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-imidazole;

1-{4-[2-(1H-imidazol-1-ylmethyl)-2-(4-methoxyphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-imidazole;

1-{4-[2-(1H-imidazol-1-ylmethyl)-2-(2-methyl-4-chlorophenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-imidazole;

1-{4-[2-(4-chlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-pyrazole;

1-{4-[2-(1H-imidazol-1-ylmethyl)-2-(4-methylphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-pyrazole;

1-{4-[2-(1H-imidazol-1-ylmethyl)-2-(4-methoxphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-pyrazole;

1-{4-[2-(4-chlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-1,2,4-triazole;

1-{4-[2-(1H-imidazol-1-ylmethyl)-2-(4-methylphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-1,2,4-triazole;and

1-{4-[2-(1H-imidazol-1-ylmethyl)-2-(4-methoxyphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-1,2,4-triazole.

EXAMPLE XX

A mixture of 8.7 parts of (4-methoxyphenyl)hydrazine hydrochloride, 8.1parts of 1-phenyl-1,3-butanediole, 7 parts of potassium carbonate and160 parts of ethanol is stirred and refluxed for 20 hours. The reactionmixture is cooled and poured onto water. The product is extracted twicewith 2,2'-oxybispropane. The combined extracts are washed with water,dried, filtered and evaporated. The residue is crystallized twice frompetroleumether. The product is filtered off and dried, yielding 7 parts(53%) of 1-(4-methoxyphenyl)-3-methyl-5-phenyl-1H-pyrazole; mp. 110° C.

EXAMPLE XXI

Following the procedure of Example XX and using an equivalent amount ofrespectively 2,2,6,6-tetramethyl-3,5-heptanedione, 2,4-pentanedione or1,3-diphenyl-1,3-propanedione in place of the 1-phenyl-1,3-butanedioneused therein the following pyrazoles are obtained:

3,5-bis(1,1-dimethylethyl)-1-(4-methoxyphenyl)-1H-pyrazole; mp. 122.6°C.;

1-(4-methoxyphenyl)-3,5-dimethyl-1H-pyrazole monohydrochloride; mp.131°-136° C.;

1-(4-methoxphenyl)-3,5-diphenyl-1H-pyrazole; mp. 119.4° C.

EXAMPLE XXII

A mixture of 17.5 parts of 2-amino-1-phenylethanone hydrochloride, 16.5parts of 1-isothiocyanato-4-methoxybenzene, 10 parts of sodium hydrogencarbonate and 200 parts of 2-propanol is stirred first for 30 minutes atroom temperature and further for 2 hours at reflux temperature. Thereaction mixture is poured onto 500 parts of water. The product isfiltered off and stirred and refluxed for 1 hour with 240 parts ofhydrochloric acid solution 10%. After cooling, the product is filteredoff, washed with water and 2-propanol, and dried, yielding 25.3 parts(90%) of 1-(4-methoxyphenyl)-5-phenyl-1H-imidazole-2-thiol; mp. 267.4°C.

EXAMPLE XXIII

A mixture of 12 parts of1-(4-methoxyphenyl)-5-phenyl-1H-imidazole-2-thiol, 10 parts ofRaney-nickel catalyst, 160 parts of ethanol, 180 parts of ethyl acetateand 36 parts of ammonium hydroxide is stirred and refluxed overnight.The solution is decanted and the residual Raney-nickel is boiled againin a mixture of 160 parts of ethanol and 180 parts of ethyl acetate. Thesolvent is decanted. The combined ethanol/ethyl acetate phases areevaporated. The residue is crystallized from a mixture of 2-propanol andwater. The product is filtered off and dried, yielding 6.5 parts (61%)of 1-(4-methoxyphenyl)-5-phenyl-1H-imidazole; mp. 105.7° C.

EXAMPLE XXIV

To a stirred solution of 17 parts of1-(4-methoxyphenyl)-1H-imidazole-2-thiol and 10.15 parts of bromoethanein 200 parts of dimethylsulfoxide are added 2.9 parts of sodium hydridedispersion 78%. The whole is stirred for 2 hours at room temperature.The reaction mixture is poured onto water and the product is extractedtwice with 2,2'-oxybispropane. The combined extracts are washed withwater, dried, filtered and acidified with 2-propanol, previouslysaturated with gaseous hydrogen chloride. The formed hydrochloride saltis filtered off and crystallized from 2-propanol. The product isfiltered off and dried, yielding 18 (81%) of2-(ethylthio)-1-(4-methoxyphenyl)-1H-imidazole monohydrochloride; mp.175° C.

EXAMPLE XXV

Following the procedure of Example XXIV and using an equivalent amountof an appropriate bromoalkane in place of the bromoethane used therein,there are prepared:

1-(4-methoxyphenyl)-2-(propylthio)-1H-imidazole monohydrochloride; mp.136.8° C.; and

1-(4-methoxyphenyl)-2-[(1-methylethyl)thio]-1H-imidazolemonohydrochloride; mp. 172.6° C.

EXAMPLE XXVI

To a stirred solution of 11 parts of1-(4-methoxyphenyl)1H-imidazole-2-thiol in 100 parts ofdimethylsulfoxide are added 1.6 parts of sodium hydride dispersion 78%.After stirring for one hour at room temperature, 6.65 parts of dimethylsulfate are added and the whole is further stirred for one hour at roomtemperature. The reaction mixture is poured onto water and the productis extracted twice with 1,1'-oxybisethane. The combined extracts arewashed with water, dried, filtered and the filtrate is acidified with2-propanol, previously saturated with gaseous hydrogen chloride. Theformed hydrochloride salt is filtered off and crystallized from2-propanol, yielding 7.8 parts (60%) of1-(4-methoxyphenyl)-2-(methylthio)-1H-imidazole monohydrochloride; mp.178° C.

EXAMPLE XXVII

To a stirred solution of 2.2 parts of1-(4-methoxyphenyl)-5-methyl-1H-imidazole-2-thiol and 0.8 parts ofsodium hydroxide in 80 parts of methanol are added 1.33 parts ofdimethyl sulfate. The whole is stirred for one hour at room temperatureand poured onto water. The product is extracted with 1,1'-oxybisethane.The extract is dried, filtered and the filtrate is acidified with2-propanol, previously saturated with gaseous hydrogen chloride. Theformed hydrochloride salt is filtered off and crystallized from2-propanol, yielding 1.8 parts (66%) of1-(4-methoxyphenyl)-5-methyl-2-(methylthio)-1H-imidazolemonohydrochloride; mp 218.3° C.

EXAMPLE XXVIII

Following the procedure of Example XXVII there is prepared1-(4-methoxyphenyl)-2-(methylthio)-5-phenyl-1H-imidazole; mp 159° C., bythe reaction of 1-(4-methoxyphenyl)-5-phenyl-1H-imidazole-2-thiol withdimethyl sulfate.

EXAMPLE XXIX

A mixture of 13.5 parts of N-(4-methoxyphenyl)hydrazinecarbothioamide,15 parts of ethanimidamide hydrochloride, 15 parts of sodium acetate and120 parts of 1-butanol is stirred and refluxed for 1 hour. The reactionmixture is cooled, 100 parts of water are added, followed by theaddition of 140 parts of petroleumether. The precipitated product isfiltered off and dried, yielding 12.5 parts (83%) of4-(4-methoxyphenyl)-5-methyl-4H-1,2,4-triazole-3-thiol; mp. 214.2° C.

EXAMPLE XXX

Following the procedure of Example XXIX and using an equivalent amountof an appropriate alkanimidamide hydrochloride in place of theethanimidamide used therein there are prepared:

5-ethyl-4-(4-methoxyphenyl)-4H-1,2,4-triazole-3-thiol; mp. 191.5° C.;and

4-(4-methoxyphenyl)-5-propyl-4H-1,2,4-triazole-3-thiol; mp. 165.4° C.

EXAMPLE XXXI

A mixture of 10.5 parts of4-(4-methoxyphenyl)-5-methyl-4H-1,2,4-triazole-3-thiol, 10 parts ofRaney-nickel catalyst, 18 parts of ammonium hydroxide and 200 parts ofmethanol is stirred and refluxed for 4 hours. The reaction mixture isdecanted while hot and the Raney-nickel catalyst is boiled in 160 partsof methanol. The latter is decanted and the combined methanol-phases areevaporated. The residue is crystallized from a mixture of4-methyl-2-pentanone and 2,2'-oxybispropane. The product is filtered offand dried, yielding 4.2 parts of4-(4-methoxyphenyl)-3-methyl-4H-1,2,4-triazole; mp. 111.9° C.

EXAMPLE XXXII

Following the procedure of Example XXXI the following4-(4-methoxyphenyl)-4H-1,2,4-triazoles are obtained by desulfurizing thecorresponding 4-(4-methoxyphenyl)-4H-1,2,4-triazole-3-thiols:

3-ethyl-4-(4-methoxyphenyl)-4H-1,2,4-triazole monohydrochloride; mp.221.2° C.; and 4-(4-methoxyphenyl)-3-propyl-4H-1,2,4-triazolemonohydrochloride.

EXAMPLE XXXIII

To a stirred solution of 2.1 parts of4-(4-methoxyphenyl)4H-1,2,4-triazole-3-thiol and 0.8 parts of sodiumhydroxide in 40 parts of methanol are added 1.33 parts of dimethylsulfate and stirring is continued for 1 hour at room temperature. Thereaction mixture is poured onto water and the product is extracted threetimes with dichloromethane. The combined extracts are washed with asaturated sodium chloride solution, dried, filtered and evaporated. Theresidue is converted into the hydrochloride salt in 2-propanol and2,2'-oxybispropane. The salt is filtered off and crystallized from2-propanol. The product is filtered off and dried, yielding 1.8 parts(70%) of 4-(4-methoxyphenyl)-3-(methylthio)-4H-1,2,4-triazolemonohydrochloride; mp. 171.5° C.

EXAMPLE XXXIV

Following the procedure of Example XXXIII there is prepared4-(4-methoxyphenyl)-3-methyl-5-(methylthio)-4H-1,2,4-triazolemonohydrochloride; mp. 165.2° C., by the reaction of4-(4-methoxyphenyl)-5-methyl-4H-1,2,4-triazole-3-thiol with dimethylsulfate.

EXAMPLE XXXV

To a stirred solution of 35.7 parts of4-(4-methoxyphenyl)3-(methylthio)-4H-1,2,4-triazole monohydrochloride in100 parts of acetic acid and 300 parts of water are added portionwise 44parts of potassium permanganate while the temperature has been kept atabout 30° C. Upon completion, stirring is continued for 2 hours at roomtemperature. The reaction mixture is decoloured with a sodium sulfitesolution and neutralized with sodium hydrogen carbonate. The whole isfiltered and the filter-cake is boiled first twice in 320 parts ofmethanol and then twice in 360 parts of ethyl acetate, while each time,the mixture is filtered. The combined filtrates are evaporated and theresidue is triturated in 200 parts of water. The product is filteredoff, washed with water and with 2-propanol, and dried, yielding 28 parts(80%) of 4-(4-methoxyphenyl)-3-(methylsulfonyl)-4H-1,2,4-triazole; mp.191.1° C.

EXAMPLE XXXVI

A mixture of 17 parts of (4-methoxyphenyl)hydrazine hydrochloride, 16.3parts of benzoyl isothiocyanate, 10 parts of N,N-diethylethanamine and130 parts of dichloromethane is stirred for 1 hour at room temperature.The mixture is washed with water and the solvent is evaporated. Thenthere are added 4.5 parts of sodium hydroxide solution 50% and 80 partsof ethanol to the residue and the whole is stirred and refluxed for 30minutes. The mixture is neutralized with concentrated hydrochloric acidand diluted with water. The precipitated product is filtered off andcrystallized from 1-butanol, yielding 13 parts (46%) of1-(4-methoxyphenyl)-5-phenyl1H-1,2,4-triazole-3-thiol; mp. 260° C.

EXAMPLE XXXVII

A mixture of 10 parts of 2-(4-methoxyphenyl)hydrazinecarbothioamide,10.6 parts of methanimidamide acetate and 80 parts of 1-butanol isstirred and refluxed for 1 hour. After cooling, water and2,2'-oxybispropane are added, whereupon the product is precipitated. Itis filtered off and dried, yielding 7.6 parts (73%) of1-(4-methoxyphenyl)-1H-1,2,4-triazole-3-thiol.

EXAMPLE XXXVIII

A mixture of 17.5 parts of 2-(4-methoxyphenyl)hydrazinecarbothioamide,10 parts of acetic acid anhydride and 90 parts of dimethylbenzene isstirred and refluxed for one hour. The reaction mixture is allowed tocool to room temperature and 2,2'-oxybispropane and water are added. Theprecipitated product is filtered off and dried, yielding 14.5 parts(89%) of acetic acid 2-(aminothioxomethyl)-1-(4-methoxyphenyl)hydrazide.

A mixture of 14.5 parts of acetic acid2-(aminothioxomethyl)-1-(4-methoxyphenyl)hydrazide, 5 parts of sodiumhydroxide and 80 parts of methanol is stirred and refluxed for 30minutes. The reaction mixture is cooled and water is added. The whole isadjusted to pH 5 with a hydrochloric acid solution. The precipitatedproduct is filtered off and dried, yielding 12.3 parts (91%) of1-(4-methoxyphenyl)-5-methyl-1H-1,2,4-triazole-3-thiol.

EXAMPLE XXXIX

Following the procedure of Example XXXVIII and using an equivalentamount of propanoic acid anhydride in place of the acetic acid anhydrideused therein there is prepared5-ethyl-1-(4-methoxyphenyl)-1H-1,2,4-triazole-3-thiol.

EXAMPLE XL

A mixture of 4.5 parts of1-(4-methoxyphenyl)-5-methyl-1H-1,2,4-triazole-3-thiol, 16 parts ofRaney-nickel catalyst, 80 parts of methanol and 27 parts of ammoniumhydroxide is stirred and refluxed overnight. The reaction mixture isfiltered and the filtrate is evaporated. The residue is converted intothe hydrobromide salt with a hydrobromic acid solution 48% in glacialacetic acid. The solvent is evaporated and the residue is triturated in2-propanone. The salt is filtered off and dried, yielding 4.9 parts(90%) of 1-(4-methoxyphenyl)-5-methyl-1H-1,2,4-triazolemonohydrobromide; mp. 185.8° C.

EXAMPLE XLI

Following the procedure of Example XL the following 1H-1,2,4-triazolesand acid addition salts thereof are obtained by desulfurizing thecorresponding 1H-1,2,4-triazole-3-thiols:

5-ethyl-1-(4-methoxyphenyl)-1H-1,2,4-triazole ethanedioate (1:1); and

1-(4-methoxyphenyl)-5-phenyl-1H-1,2,4-triazole; mp. 98.1° C.

EXAMPLE XLII

A mixture of 8 parts of 1-(4-methoxyphenyl)-1H-1,2,4-triazole-3-thiol,3.1 parts of sodium hydroxide and 40 parts of methanol is stirred for 30minutes at room temperature. Then there are added 4.9 parts of dimethylsulfate and stirring at room temperature is continued for 3 hours. Wateris added to the reaction mixture and the product is extracted twice with1,1'-oxybisethane. The combined extracts are dried, filtered andevaporated. The residue is purified by column-chromatography over silicagel using trichloromethane as eluent. The pure fractions are collectedand the eluent is evaporated. The residue is crystallized from2,2'-oxybispropane, yielding 5.6 parts (65%) of1-(4-methoxyphenyl)-3-(methylthio)-1H-1,2,4-triazole; mp. 54.9° C.

EXAMPLE XLIII

Following the procedure of Example XLII there is prepared1-(4-methoxyphenyl)-5-methyl-3-(methylthio)-1H-1,2,4-triazolemonohydrochloride; mp. 179.3° C., by the reaction of1-(4-methoxyphenyl)-5-methyl-1H-1,2,4-triazole-3-thiol with dimethylsulfate.

EXAMPLE XLIV

A mixture of 6 parts of1-(4-methoxyphenyl)-5-methyl-1H-1,2,4-triazole-3-thiol, 2.2 parts ofsodium hydroxide and 60 parts of methanol is stirred for 30 minutes atroom temperature. Then there are added 4.4 parts of bromoethane andstirring is continued for 3 hours. Water is added and the product isextracted with 2,2'-oxybispropane. The extract is dried, filtered andevaporated. The residue is converted into the hydrochloride salt in4-methyl-2-pentanone and 2,2'-oxybispropane. The salt is filtered offand crystallized from a mixture of 2-propanol and 2,2'-oxybispropane,yielding 3 parts (38%) of3-(ethylthio)-1-(4-methoxyphenyl)-5-methyl-1H-1,2,4-triazolemonohydrochloride; mp. 149.2° C.

EXAMPLE XLV

Following the procedure of Example XLIV and using equivalent amounts ofthe appropriate starting materials there are prepared:

3-(ethylthio)-1-(4-methoxyphenyl)-1H-1,2,4-triazole as a residue; and

5-ethyl-3-(ethylthio)-1-(4-methoxyphenyl)-1H-1,2,4-triazolemonohydrochloride; mp. 123.4° C.

EXAMPLE XLVI

A mixture of 14 parts of 2-(ethylthio)-1-(4-methylphenyl)-1H-imidazolemonohydrochloride and 113 parts of hydrobromic acid solution 48% inglacial acetic acid is stirred and refluxed for 3 hours. The reactionmixture is evaporated and the residue is dissolved in water. Thesolution is neutralized with sodium hydrogen carbonate. The precipitatedproduct is filtered off and crystallized from 2-propanol, yielding 8.3parts (72.5%) of 4-[2-(ethylthio-1H-imidazol-1-yl]phenol; mp. 165.2° C.

EXAMPLE XLVII

Following the procedure of Example XLVI the following phenols areprepared starting from the corresponding methoxy substituted compounds:

4-[2-(methylthio)-1H-imidazol-1-yl]phenol; mp. 204° C.;

4-[2-(propylthio)-1H-imidazol-1-yl]phenol; mp. 118.1° C.;

4-{2-[(1-methylethyl)thio]-1H-imidazol-1-yl}phenol; mp. 162.9° C.;

4-(5-methyl-1H-imidazol-1-yl)phenol; mp. 245.2° C.;

4-[5-methyl-2-(methylthio)-1H-imidazol-1-yl]phenol; mp. 255.5° C.;

4-[2-(methylthio)-5-phenyl-1H-imidazol-1-yl]phenol; mp. 236.3° C.;

4-(5-phenyl-1H-imidazol-1-yl)phenol; mp. 301°-310° C.;

4-(3,5-dimethyl-1H-pyrazol-1-yl)phenol; mp. 163.3° C.;

4-(3,5-diphenyl-1H-pyrazol-1-yl)phenol 2-propanolate (2:1); mp. 215.6°C.;

4-[3,5-bis(1,1-dimethylethyl)-1H-pyrazol-1-yl]phenol; mp. 268.7° C.;

4-(3-methyl-5-phenyl-1H-pyrazol-1-yl)phenol; mp. 209.7° C.;

4-(3-methyl-1H-pyrazol-1-yl)phenol;

4-[3-(ethylthio)-1H-1,2,4-triazol-1-yl]phenol; mp. 166.6° C.;

4-[3-(methylthio)-1H-1,2,4-triazol-1-yl]phenol; mp. 170° C.;

4-[5-ethyl-3-(ethylthio)-1H-1,2,4-triazol-1-yl]phenol monohydrobromide;mp. 171.2° C.;

4-[5-methyl-3-(methylthio)-1H-1,2,4-triazol-1-yl]phenolmonohydrobromide; mp. 239.2° C.;

4-[3-(ethylthio)-5-methyl-1H-1,2,4-triazol-1-yl]phenol monohydrobromide;

4-(5-phenyl-1H-1,2,4-triazol-1-yl)phenol monohydrobromide; mp. 261.6°C.;

4-(5-methyl-1H-1,2,4-triazol-1-yl)phenol monohydrobromide; mp. 262.4°C.;

4-(5-ethyl-1H-1,2,4-triazol-1-yl)phenol; mp. 136.7° C,;

4-(3-methyl-4H-1,2,4-triazol-4-yl)phenol; mp. 289.5° C.;

4-(3-ethyl-4H-1,2,4-triazol-4-yl)phenol; mp. 239.9° C.;

4-[3-methyl-5-(methylthio)-4H-1,2,4-triazol-4-yl]phenol; mp. 261.3° C.;

4-[3-(methylsulfonyl)-4H-1,2,4-triazol-4-yl]phenol; mp. 211.5° C.;

4-(3-propyl-4H-1,2,4-triazol-4-yl)phenol; and

4; -[3-(methylthio)-4H-1,2,4-triazol-4-yl]phenol; mp. 176.2° C.

EXAMPLE XLVIII

A mixture of 174 parts of 2-bromo-1-(3-chlorophenyl)ethanone, 81 partsof 1,2,3-propanetriol, 7.4 parts of 4-methylbenzenesulfonic acid, 94parts of 1-butanol and 528 parts of benzene is stirred and refluxed for20 hours with water-separator. The reaction mixture is poured onto adiluted sodium hydroxide solution and the layers are separated. Theaqueous phase is extracted twice with methylbenzene. The combinedorganic phases are washed twice with water, dried, filtered andevaporated, yielding 238 parts of cis+trans-2-(bromomethyl)-2-(3-chlorophenyl)-1,3-dioxolane-4-methanol as aresidue.

238 Parts of cis+trans-2-(bromomethyl)-2-(3-chlorophenyl)-1,3-dioxolane-4-methanol aredisssolved in a mixture of 144 parts of pyridine and 1135 parts oftrichloromethane and the solution is cooled to about 5° C. Then thereare added dropwise 149 parts of benzoyl chloride at a temperature below10° C. Upon completion, stirring is continued for 2 hours at roomtemperature. The reaction mixture is poured onto water and the layersare separated. The aqueous phase is extracted twice withtrichloromethane. The combined extracts are washed twice with watr,dried, filtered and evaporated. The residue is stirred for a few hoursin hexane. The precipitated product is filtered off and dried at theair, yielding 128 parts ofcis+trans-[2-(bromomethyl)-2-(3-chlorophenyl)-1,3-dioxolan-4-ylmethyl]benzoate.

A mixture of 26 parts of 1H-imidazole and 68.5 parts of sodiummethanolate solution 30% is stirred and refluxed for 15 minutes. 90Parts of N,N-dimethylformamide are added and the methanol is distilledoff till an internal temperature of 130° C. Then there is added dropwisea solution of 1025 parts of cis+trans-[2-(bromomethyl)-2-(3-chlorophenyl)-1,3-dioxolan-4-ylmethyl] benzoate in225 parts of N,N-dimethylformamide. Upon completion, stirring iscontinued for 3 hours at reflux. The reaction mixture is cooled, wateris added and the product is extracted three times with4-methyl-2-pentanone. The combined extracts are washed twice with water,dried, filtered and evaporated, yielding 43 parts ofcis+trans-[2-(3-chlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl]benzoate as a residue.

A mixture of 45 parts ofcis+trans-[2-(3-chlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl]benzoate, 36 parts of sodium hydroxide solution 50%, 600 parts of1,4-dioxane and 200 parts of water is stirred and refluxed for 1 hour.The reaction mixture is cooled and poured onto water. Trichloromethaneis added and the layers are separated. The organic phase is washed withwater, dried, filtered and evaporated. The residue is converted into thehydrochloride salt in 2-propanone and 2-propanol. After stirring for 2hours in an ice-bath, the salt is filtered off and dried, yielding 14parts ofcis+trans-2-(3-chlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolane-4-methanolmonohydrochloride; mp. 198.3° C.

A mixture of 68 parts ofcis+trans-2-(3-chlorophenyl)-2-(1H-imidazol1-ylmethyl)-1,3-dioxolane-4-methanoland 570 parts of pyridine is cooled to 0° C. The ice-bath is taken awayand 26.3 parts of methanesulfonyl chloride are added dropwise(exothermic reaction: temp. rises to 20° C.). Upon completion, stirringis continued for 3 hours at room temperature. The reaction mixture ispoured onto water and the product is extracted with trichloromethane.The extract is dried, filtered and evaporated. The residue is convertedinto the hydrochloride salt in 2-propanone and 2-propanol. The salt isfiltered off and crystallized from 2-propanol, yielding 32 parts of[2-(3-chlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl]methanesulfonatemonohydrochloride.

EXAMPLE IL

Following the procedure of Example XLVIII and using equivalent amountsof the appropriate starting materials there is prepared:

[2-(1H-imidazol-1-ylmethyl)-2-(4-methoxyphenyl)-1,3-dioxolan-4-ylmethyl]methanesulfonate.

EXAMPLE L

A mixture of 1.6 parts of 1H-1,2,4-triazole, 54 parts ofN,N-dimethylformamide and 45 parts of benzene is stirred and refluxedfor 2 hours. After cooling, 0.78 parts of sodium hydride dispersion 78%are added and the whole is stirred for 30 minutes at room temperature.Then there are added 8.9 parts ofcis-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-ylmethylbenzoate and stirring is continued overnight at 150° C. The reactionmixture is cooled and poured onto water. The product is extracted threetimes with benzene. The combined extracts are washed twice with water,dried, filtered and evaporated, yielding 8.5 parts ofcis-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl]benzoate as a residue.

A mixture of 289 parts ofcis-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl]benzoate, 200 parts of sodium hydroxide solution 50%, 1500 parts of1,4-dioxane and 300 parts of water is stirred and refluxed for 2 hours.The reaction mixture is cooled and poured onto water. The product isextracted with dichloromethane. The extract is washed with water, dried,filtered and evaporated. The residue is purified by columnchromatographyover silica gel using a mixture of trichloromethane and methanol (95:5by volume) as eluent. The first fraction is collected and the eluent isevaporated, yielding 89 parts ofcis-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanol;mp. 138.2° C.

A mixture of 30.6 parts ofcis-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanoland 75 parts of pyridine is stirred at room temperature and there areadded dropwise 17.2 parts of methanesulfonyl chloride. Upon completion,stirring is continued overnight at room temperature. The reactionmixture is poured onto ice-water and the product is extracted twice withdichloromethane. The combined extracts are washed twice with a dilutedhydrochloric acid solution and twice with water, dried, filtered andevaporated. The residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and methanol (95:5 by volume) aseluent. The first fraction is collected and the eluent is evaporated,yielding 21 parts ofcis-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl]methanesulfonate; mp. 98° C.

EXAMPLE LI

Following the procedure of Example VIII and using equivalent amounts ofthe appropriate starting materials the following compounds of formula Ihaving the cis-configuration and acid addition salts thereof areprepared:

    ______________________________________                                         ##STR70##                                                                    Y              Salt or base form                                                                            m. p. °C.                                ______________________________________                                         ##STR71##     2HNO.sub.3     191.9                                            ##STR72##     2HNO.sub.3     166.4                                            ##STR73##     2HNO.sub.3     172.3                                            ##STR74##     base           135.4                                            ##STR75##     2HNO.sub.3     156.9                                            ##STR76##     2HNO.sub.3     137.8                                            ##STR77##     2HNO.sub.3     148.6                                            ##STR78##     2HNO.sub.3     143.7                                            ##STR79##     2HNO.sub.3     166.6                                            ##STR80##     2HNO.sub.3     192.1                                            ##STR81##     2HNO.sub.3     152.2                                            ##STR82##     base           160.1                                            ##STR83##     HNO.sub.3      161.4                                            ##STR84##     2HNO.sub.3     164.9                                            ##STR85##     HNO.sub.3      157.2                                            ##STR86##     base           138.3                                            ##STR87##     base           167.1                                            ##STR88##     base           192.1                                            ##STR89##     2HCl           196.2                                            ##STR90##     HNO.sub.3.H.sub.2 O                                                                          162.1                                            ##STR91##     HNO.sub.3      162.3                                            ##STR92##     base 1/2 H.sub.2 O                                                                           123.5                                            ##STR93##     HNO.sub.3      187.3                                            ##STR94##     HCl            209.9                                            ##STR95##     2HNO.sub.3     151.3                                            ##STR96##     2HNO.sub.3     157                                              ##STR97##     base H.sub.2 O 126                                              ##STR98##     2(COOH).sub.2  148.7                                            ##STR99##     2HNO.sub.3     177.4                                           ______________________________________                                    

example lii

following the procedure of Example VIII and being equivalent amounts ofthe appropriate starting materials the following compounds of formula Iand acid addition salts thereof are still prepared:

cis ortans-1-{4-[2-(3-chlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-imidazoleethanedioate (1:2); mp. 175.8° C.;

cis-1-{4-[2-(1H-imidazol-1-ylmethyl)-2-(4-methoxyphenyl)-1,3-dioxolan-4-ylmethoxy]-phenyl}-1H-imidazole;mp. 120.4° C.;

cis-1-{3-[2-(2,4-dichlorophenyl)-2-(1-H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-imidazoleethanedioate (1:2); mp. 132.1° C.; and

cis-1-{2-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-imidazoleethanedioate (1:2); mp. 172.4° C.

EXAMPLE LIII

To a stirred and cooled (ice-bath) solution of 4 parts ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-3-(methylthio)-4H-1,2,4-triazolein 130 parts of dichloromethane are added 1.5 parts of3-chlorobenzeneperoxoic acid and stirring is continued for 2 hours. Thereaction mixture is washed with a sodium hydrogen carbonate solution,dried, filtered and evaporated. The residue is purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane and methanol (98:2 by volume) as eluent. The purefractions are collected and the eluent is evaporated. The residue isconverted into the ethanedioate salt in 2-propanol. The salt is filteredoff and crystallized from absolute ethanol, yielding 2.7 parts (52%) ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-3-(methylsulfinyl)-4H-1,2,4-traizoleethanedioate (2:3); mp. 142.7° C.

EXAMPLE LIV

Following the procedure of Example LIII there is preparedcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-3-methyl-5-(methylsulfinyl)-4H-1,2,4-triazoleethanedioate (1:1).2-propanplate (2:1); mp. 116.4° C. by the reaction ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-3-methyl-5-(methylthio)-4H-1,2,4-triazolewith 3-chlorobenzeneperoxoic acid.

EXAMPLE LV

To a stirred solution of 1.35 parts of 1-bromopropane and 5 parts ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4H-1,2,4-triazole-3-thiolin 100 parts of dimethylsulfoxide are added 0.32 parts of sodium hydridedispersion 78%. The whole is stirred for 3 hours at room temperature.The reaction mixture is poured onto water and the product is extractedtwice with trichloromethane. The combined extracts are washed withwater, dried, filtered and evaporated. The residue is purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane and methanol (98:2 by volume) as eluent. The purefractions are collected and the eluent is evaporated. The residue isconverted into the ethanedioate salt in 2-propanol and2,2'-oxybispropane. The salt is filtered off and crystallized from2-propanone, yielding 3.1 parts (42%) ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-3-(propylthio)-4H-1,2,4-triazole ethanedioate (1:2); mp. 146.9° C.

EXAMPLE LVI

Following the procedure of Example LV there is preparedcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}3-[(1-methylethyl)thio]-4H-1,2,4-triazoleethanedioate (1:2); mp. 140.2° C. by the reaction ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4H-1,2,4-triazole-3-thiolwith 2-bromopropane.

EXAMPLE LVII

To a stirred solution of 1.33 parts of dimethyl sulfate in 100 parts ofdimethylsulfoxide are added 0.32 parts of sodium hydride dispersion 78%.After stirring for one hour at about 50° C., 4.3 parts ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-oneare added. The whole is stirred for one hour at room temperature. Thereaction mixture is poured onto water and the product is extracted twicewith trichloromethane. The combined extracts are washed with water,dried, filtered and evaporated. The residue is converted into thenitrate salt in 2-propanol and 1,1'-oxybisethane. The salt is filteredoff and crystallized from ethanol, yielding 2.6 parts (53%) ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-2,4-dihydro-2,5-dimethyl-3H-1,2,4-triazol-3-onemononitrate; mp. 208.6° C.

EXAMPLE LVIII

To a stirred solution of 1.74 parts of bromoethane and 6 parts ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-onein 100 parts of dimethylsulfoxide are added 0.5 parts of sodium hydridedispersion 78% and the whole is stirred for 2 hours at about 40° C. Thereaction mixture is poured onto water and the product is extracted withtrichloromethane. The extract is washed with water, dried, filtered andevaporated. The residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and methanol (98:2 by volume) aseluent. The pure fractions are collected and the eluent is evaporated.The residue is crystallized from a mixture of 4-methyl-2-pentanone and2,2'-oxybispropane. The product is filtered off and dried, yielding 4.1parts (66%) ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-2-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one;mp. 112° C.

EXAMPLE LIX

Following the procedure of Example LVIII and using equivalent amounts ofthe appropriate starting materials there are prepared:

cis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-2,4-dihydro-5-methyl-2-(1-methylethyl)-3H-1,2,4-triazol-3-one;mp. 170.7° C. by the reaction ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-onewith 2-bromopropane; and

cis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-2-ethyl-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one;mp. 154.5° C. by the reaction ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-phenyl}-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-onewith bromoethane.

EXAMPLE LX

A mixture of 1 part of sodium azide, 2 parts of1,1',1"-[methylidynetris(oxy)]trisethane, 4.2 parts ofcis-4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]benzenamineand 50 parts of acetic acid is stirred and heated for 4 hours at 70° C.The reaction mixture is cooled, poured onto water and neutralized withpotassium carbonate. The product is extracted with dichloromethane. Theextract is dried, filtered and evaporated. The residue is crystallizedfrom a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. Theproduct is filtered off and recrystallized from 4-methyl-2-pentanone,yielding 2.9 parts (61%) ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl-methyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-tetrazole;mp. 132.6° C.

EXAMPLE LXI

A mixture of 1.3 parts of sodium azide, 4.6 parts ofcis-1-[2-(2,4-dichlorophenyl)-4-(4-isothiocyanatophenoxymethyl)-1,3-dioxolan-2-ylmethyl]-1H-imidazoleand 80 parts of methanol is stirred and refluxed for one hour. Thenthere is added one part of sodium hydroxide and stirring at reflux iscontinued for one hour. The reaction mixture is cooled, poured ontowater and washed with 1,1'-oxybisethane. The aqueous phase is acidifiedwith hydrochloric acid till pH=4. The precipitated product is filteredoff and crystallized from 1-butanol, yielding 2.8 parts (55%) ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-tetrazole-5-thio;mp. 211.7° C.

EXAMPLE LXII

A mixture of 5 parts of ethanimidamide hydrochloride, 5 parts ofcis-N-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}hydrazinecarbothioamide,5 parts of sodium acetate and 60 parts of 1-butanol is stirred andrefluxed for 30 minutes. The reaction mixture is cooled, 100 parts ofwater and 210 parts of 2,2'-oxybispropane are added and the whole isstirred for 30 minutes at room temperature. The precipitated product isfiltered off, washed with water and with 2-propanol and crystallizedfrom 1-butanol. The product is filtered off and boiled in 80 parts ofmethanol. After cooling, it is filtered off again and dried for 2 daysat 80° C., yielding 3 parts ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-5-methyl-4H-1,2,4-triazole-3-thiol;mp. 247.6° C.

EXAMPLE LXIII

A mixture of 60 parts ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-imidazoleand 900 parts of ethyl acetate is stirred and heated to reflux till allsolid enters solution. After cooling at about 50° C., there are addeddropwise 45 parts of 2-propanol, previously saturated with hydrogenchloride. After stirring overnight at room temperature, the formedhydrochloride salt is filtered off and dried in vacuo at 45° C.,yielding 57 parts (81%) ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-imidazoledihydrochloride; mp. 238.7° C.

EXAMPLE LXIV

To a stirred mixture of 3.2 parts of 4-(1H-imidazol-1-yl)phenol and 100parts of dimethylsulfoxide are added 0.7 parts of sodium hydridedispersion 76.5% and the whole is stirred for 30 minutes at roomtemperature. Then there are added 8.2 parts ofcis-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl]methanesulfonateand stirring is continued for 3 hours at 130° C. The reaction mixture iscooled, poured onto water and the product is extracted withdichloromethane. The extract is washed with water, dried, filtered andevaporated. The residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and methanol (97:3 by volume) aseluent. The pure fractions are collected and the eluent is evaporated.The residue is crystallized from 4-methyl-2-pentanone. The product isfiltered off and dried, yielding 4.4 parts ofcis-1-{2-(2,4-dichlorophenyl)-4-[4-(1H-imidazol-1-yl)phenoxymethyl]-1,3-dioxolan-2-ylmethyl}-1H-1,2,4-triazole; mp. 128.8° C.

EXAMPLE LXV

Following the procedure of Example LXIV and using equivalent amounts ofthe appropriate starting materials there are prepared:

cis-1-[2-(2,4-dichlorophenyl)-4-{4-[2-(methylthio)-1H-imidazol-1-yl]phenoxymethyl}-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazole;mp. 185.6° C.;

cis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-3-(methylthio)-4H-1,2,4-triazole;mp. 184.7° C.; and

cis-1-[2-(2,4-dichlorophenyl)-4-{4-[2-(ethylthio)-1H-imidazol-1-yl]phenoxymethyl}-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazoledinitrate; mp. 149.6°-150.8° C.

EXAMPLE LXVI

Following the procedure of Example XLVIII and using equivalent amountsof the appropriate starting materials the following methanesulfonatesare prepared:

[2-(4-methoxyphenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl]methanesulfonate;

[2-phenyl-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl]methanesulfonate;

[2-(4-chlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl]methanesulfonate;

[2-(4-bromophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl]methanesulfonate;

[2-(4-fluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl]methanesulfonate;

[2-(4-methylphenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl]methanesulfonate;and

[2-(4-methoxyphenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl]methanesulfonate.

EXAMPLE LXVII

Following the procedure of Example VIII and using equivalent amounts ofthe appropriate starting materials the following compounds of formula(I) are still prepared.

1-{2-(2,4-dichlorophenyl)-4-[2-(1H-pyrrol-1-yl)phenoxymethyl]-1,3-dioxolan-2-ylmethyl}-1H-imidazole;

1-{2-(3-chlorophenyl)-4-[4-(1H-pyrrol-1-yl)phenoxymethyl]-1,3-dioxolan-2-ylmethyl}-1H-imidazole;

1-{2-(4-methoxyphenyl)-4-[4-(1H-pyrrol-1-yl)phenoxymethyl]-1,3-dioxolan-2-ylmethyl}-1H-imidazole;

1-{2-(4-methylphenyl)-4-[4-(1H-pyrrol-1-yl)phenoxymethyl]-1,3-dioxolan-2-ylmethyl}-1H-imidazole;

1-{2-(2,4-dichlorophenyl)-4-[4-(1H-pyrrol-1-yl)phenoxymethyl]-1,3-dioxolan-2-ylmethyl}-1H-1,2,4-triazole;

1-{2-(2,4-dichlorophenyl)-4-[2-(1H-pyrrol-1-yl)phenoxymethyl]-1,3-dioxolan-2-ylmethyl}-1H-1,2,4-triazole;

1-{2-(4-methoxypenyl)-4-[4-(1H-pyrrol-1-yl)phenoxymethyl]-1,3-dioxolan-2-ylmethyl}-1H-1,2,4-triazole;

1-{2-(4-methylphenyl)-4-[4-(1H-pyrrol-1-yl)phenoxymethyl]-1,3-dioxolan-2-ylmethyl}-1H-1,2,4-triazole;

1-{3-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-pyrazole;

1-{2-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-pyrazole;

1-{4-[2-(3-chlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,2-dioxolan-4-ylmethoxy]phenyl}-1H-pyrazole;

1-{2-(2,4-dichlorophenyl)-4-[4-(1H-pyrazol-1-yl)phenoxymethyl]-1,3-dioxolan-2-ylmethyl}-1H-1,2,4-triazole;

1-{2-(4-methylphenyl)-4-[4-(1H-pyrazol-1-yl)phenoxymethyl]-1,3-dioxolan-2-ylmethyl}-1H-1,2,4-triazole;

1-{3-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl-1H-1,2,4-triazole;

1-{2-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-1,2,4-triazole;

1-{4-[2-(3-chlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-1,2,4-triazole;

1-{4-[2-(1H-imidazol-1-ylmethyl)-2-(4-methylphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-1,2,4-triazole;

1-{4-[2-(1H-imidazol-1-ylmethyl)-2-(4-methoxyphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-1,2,4-triazole;

1-{2-(2,4-dichlorophenyl)-4-[4-(1H-imidazol-1-yl)phenoxymethyl]-1,3-dioxolan-2-ylmethyl}-1H-1,2,4-triazole;

1-{2-(2,4-dichlorophenyl)-4-[3-(1H-imidazol-1-yl)phenoxymethyl]-1,3-dioxolan-2-ylmethyl}-1H-1,2,4-triazole;

1-{2-(2,4-dichlorophenyl)-4-[2-(1H-imidazol-1-yl)phenoxymethyl]-1,3-dioxolan-2-ylmethyl}-1H-1,2,4-triazole;

1-{4-[4-(1-H-imidazol-1-yl)phenoxymethyl]-2-(4-methylphenyl)-1,3-dioxolan-2-ylmethyl}-1H-1,2,4-triazole;

1-{4-[4-(1H-imidazol-1-yl)phenoxymethyl]-2-(4-methoxyphenyl)-1,3-dioxolan-2-ylmethyl}-1H-1,2,4-triazole;

4-{3-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4H-1,2,4-triazole;

4-{2-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4H-1,2,4-triazole;

4-{4-[2-(1H-imidazol-1-ylmethyl)-2-(4-methylphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4H-1,2,4-triazole;

4-{4-[2-(1H-imidazol-1-ylmethyl)-2-(4-methoxyphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4H-1,2,4-triazole;

1-{2-(2,4-dichlorophenyl)-4-[2-(4H-1,2,4-triazol-4-yl)phenoxymethyl]-1,3-dioxolan-2-ylmethyl}-1H-1,2,4-triazole;

1-{2-(4-methylphenyl)-4-[4-(4H-1,2,4-triazol-4-yl)phenoxymethyl]-1,3-dioxolan-2-ylmethyl}-1H-1,2,4-triazole;and

1-{2-(4-methoxyphenyl)-4-[4-(4H-1,2,4-triazol-4-yl)phenoxymethyl]-1,3-dioxolan-2-ylmethyl}-1H-1,2,4-triazole.

EXAMPLE LXVIII

Following the procedure of Example V and using equivalent amounts of theappropriate starting materials there are prepared:

3-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]benzenamine;

2-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]benzenamine;

4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]benzenamine;

4-[2-(1H-imidazol-1-ylmethyl)-2-(4-methylphenyl)-1,3-dioxolan-4-ylmethoxy]benzenamine;and

4-[2-(1H-imidazol-1-ylmethyl)-2-(4-methoxyphenyl)-1,3-dioxolan-4-ylmethoxy]benzenamine.

EXAMPLE LXIX

Following the procedure of Example LX and using equivalent amounts ofthe appropriate starting materials there are prepared:

1-{3-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-tetrazole;

1-{2-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-tetrazole;

1-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-tetrazole;

1-{4-[2-(1H-imidazol-1-ylmethyl)-2-(4-methylphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-tetrazole;and

1-{4-[2-(1H-imidazol-1-ylmethyl)-2-(4-methoxyphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-tetrazole.

EXAMPLE LXX

Following the procedure of Example VI and using equivalent amounts ofthe appropriate starting materials there are prepared:

N-{3-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenoxy}hydrazinecarboxamide;

N-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}hydrazinecarboxamide;

N-{4-[2-(1h-imidazol-1-ylmethyl)-2-(4-methylphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}hydrazinecarboxamide;and

N-{4-[2-(1h-imidazol-1-ylmethyl)-2-(4-methoxyphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}hydrazinecarboxamide.

EXAMPLE LXXI

Following the procedure of Example XIV and using equivalent amounts ofthe appropriate starting materials there are prepared:

4-{3-[2-(2,4-dichlorophenyl9-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-one;

4-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-one;

4-{4-[2-(1H-imidazol-1-ylmethyl)-2-(4-methylphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-one;and

4-{4-[2-(1H-imidazol-1-ylmethyl)-2-(4-methoxyphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-one.

EXAMPLE LXXII

Following the procedure of the first step of Example VII and usingequivalent amounts of the appropriate starting materials there areprepared:

1-[2-(2,4-dichlorophenyl)-4-(3-isothiocyanatophenoxymethyl)-1,3-dioxolan-2-ylmethyl]-1H-imidazole;

1-[2-(2,4-dichlorophenyl)-4-(4-isothiocyanatophenoxymethyl)-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazole;

1-[4-(4-isothiocyanatophenoxymethyl)-2-(4-methylphenyl)-1,3-dioxolan-2-ylmethyl]-1H-imidazole;and

1-[4-(4-isothiocyanatophenoxymethyl)-2-(4-methoxyphenyl)-1,3-dioxolan-2-ylmethyl]-1H-imidazole.

EXAMPLE LXXIII

Following the procedure of Example LXI and using equivalent amounts ofthe appropriate starting materials there are prepared:

1-{3-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-tetrazol-5-thiol;

1-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-tetrazole-5-thiol;

1-{4-[2-(1H-imidazol-1-ylmethyl)-2-(4-methylphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-tetrazole-5-thiol;and

1-{4-[2-(1H-imidazol-1-ylmethyl)-2-(4-methoxyphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-tetrazole-5-thiol.

EXAMPLE LXXIV

Following the procedure of the second step of Example VII and usingequivalent amounts of the appropriate starting materials there areprepared:

N-{3-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}hydrazinecarbothioamide;

N-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}hydrazinecarbothioamide;

N-{4-[2-(1h-imidazol-1-ylmethyl)-2-(4-methylphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}hydrazinecarbothioamide;and

N-{4-[2-(1h-imidazol-1-ylmethyl)-2-(4-methoxyphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}hydrazinecarbothioamide.

EXAMPLE LXXV

Following the procedure of Example XVII and using equivalent amounts ofthe appropriate starting materials there are prepared:

4-{3-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4H-1,2,4-triazole-3-thiol;

4-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4H-1,2,4-triazole-3-thiol;

4-{4-[2-(1H-imidazol-1-ylmethyl)-2-(4-methylphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4H-1,2,4-triazole-3-thiol;and

4-{4-[2-(1H-imidazol-1-ylmethyl)-2-(4-methoxyphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4H-1,2,4-triazole-3-thiol.

EXAMPLE LXXVI

A mixture of 17 parts of (4-methoxyphenyl)hydrazine hydrochloride, 14parts of 4,4-dimethoxy-2-butanone, 14 parts of potassium carbonate and240 parts of ethanol is stirred and refluxed for 2 hours. The reactionmixture is evaporated and the residue is stirred and refluxed for 1 hourwith 200 parts of a hydrochloric acid solution 10%. The solvent isevaporated and the residue is neutralized with ammonium hydroxide. Theproduct is extracted three times with 2,2'-oxybispropane. The combinedextracts are washed with water, dried, filtered and evaporated. Theresidue is purified by column-chromatography over silica gel usingtrichloromethane as eluent. The pure fractions are collected and theeluent is evaporated. The residue is crystallized from hexane. Theproduct is filtered off and dried, yielding 2.4 parts of1-(4-methoxyphenyl)-3-methyl-1H-pyrazole.

EXAMPLE LXXVII

Following the procedure of Example LXIV and using equivalent amounts ofthe appropriate starting materials there is prepared:

cis-1-{2-(2,4-dichlorophenyl)-4-[4-(3-methyl-1H-pyrazol-1-yl)phenoxymethyl]-1,3-dioxolan-2-ylmethyl}-1H-1,2,4-triazole;mp. 148.6° C.

We claim:
 1. A chemical compound selected from the group consisting of an azole derivative having the formula: ##STR100## and the pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof, wherein:Q is CH; Ar is a member selected from the group consisting of phenyl and substituted phenyl, said substituted phenyl having from 1 to 3 substituents independently selected from the group consisting of halo, lower alkyl and lower alkyloxy; and the radical Y is a member selected from the group consisting of:a 1H-pyrrol-1-yl radical of the formula ##STR101## a 1H-pyrazol-1-yl radical of the formula ##STR102## wherein R₁ is selected from the group consisting of hydrogen, lower alkyl, lower alkylthio and phenyl, and, R₂ is selected from the group consisting of hydrogen, lower alkyl and phenyl; and a 1H-imidazol-1-yl radical of the formula ##STR103## wherein R₃ is selected from the group consisting of hydrogen, lower alkyl, phenyl, lower alkylthio, lower alkylsulfinyl and lower alkylsulfonyl, R₄ is selected from the group consisting of hydrogen, lower alkyl and phenyl, and, R₅ is selected from the group consisting of hydrogen and phenyl.
 2. A chemical compound selected from the group consisting of 1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl} -1H-imidazole and the pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof.
 3. A chemical compound selected from the group consisting of 1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-pyrazole and the pharmaceutically acceptable acid additions salts and stereochemically isomeric forms thereof.
 4. A chemical compound selected from the group consisting of cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1H-imidazole and the pharmaceutically acceptable acid addition salts thereof.
 5. A composition for combatting the growth of a microorganism selected from the group consisting of fungus and bacterium comprising an inert carrier material and as an active ingredient an effective amount of a compound selected from the group consisting of an azole derivative having the formula: ##STR104## and the pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof, wherein:Q is CH; Ar is a member selected from the group consisting of phenyl and substituted phenyl, said substituted phenyl having from 1 to 3 substituents independently selected from the group consisting of halo, lower alkyl and lower alkyloxy; and the radical Y is a member selected from the group consisting of:a 1H-pyrrol-1-yl radical of the formula ##STR105## a 1H-pyrazol-1-yl radical of the formula ##STR106## wherein R₁ is selected from the group consisting of hydrogen, lower alkyl, lower alkylthio and phenyl, and, R₂ is selected from the group consisting of hydrogen, lower alkyl and phenyl; and a 1H-imidazol-1-yl radical of the formula ##STR107## wherein R₃ is selected from the group consisting of hydrogen, lower alkyl, phenyl, lower alkylthio, lower alkylsulfinyl and lower alkylsulfonyl, R₄ is selected from the group consisting of hydrogen, lower alkyl and phenyl, and, R₅ is selected from the group consisting of hydrogen and phenyl. 